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The Role of Immune Cells in the Tumor Microenvironment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 26916

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Dr. Aurélie Tchoghandjian

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Institute of Neurophysiopathology, Aix-Marseille University, CNRS, INP, 13005 Marseille, France
Interests: glioblastomas; cancer stem cells; tumor microenvironment; preclinical models; inhibitor of apoptosis; cell death; immune cells
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Dear Colleagues,

For several years now, with the emergence of immunotherapy, the role of immune cells in tumor progression has gained more and more attention. We have learnt that immune cells are key actors of treatment resistance, and the re-establishment of an immunocompetent microenvironment is a therapeutic challenge. The role of immune cells in tumor progression is nevertheless complex and bivalent depending on the local tumor microenvironment. We need now to go further and to better identify the role of immune cell subsets to propose new therapeutic strategies. We also know that immune cells and tumor vascularization are closely related, as are immune cells and tumor stem cells. Particular attention will address the cross talk between tumor stem cells and immune cells, as well as tumor vascularization and immune cells. Furthermore, brain tumors have a specific immune environment with the presence of local immune cells, such as microglia cells. Strong connections exist between microglia cells and astrocytes supporting and promoting immunosuppression. Therefore, to better understand immune brain microenvironment, studies dealing with brain tumors are welcome.

Dr. Aurélie Tchoghandjian
Guest Editor

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Keywords

tumor immunosuppression
tumor progression
role of immune cell subtypes
immune cells interactions
microglia
astrocytes
tumor vessels

Published Papers (10 papers)

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Research

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15 pages, 7183 KiB

Open AccessArticle

Spatial Distribution of Immune Cells in Primary and Recurrent Glioblastoma: A Small Case Study

by Delphine Loussouarn, Lisa Oliver, Celine Salaud, Edouard Samarut, Raphaël Bourgade, Christophe Béroud, Emilie Morenton, Dominique Heymann and Francois M. Vallette

Cancers 2023, 15(12), 3256; https://doi.org/10.3390/cancers15123256 - 20 Jun 2023

Cited by 3 | Viewed by 1414

Abstract

Only a minority of patients with glioblastoma (GBM) respond to immunotherapy, and always only partially. There is a lack of knowledge on immune distribution in GBM and in its tumor microenvironment (TME). To address the question, we used paired primary and recurrent tumors from GBM patients to study the composition and the evolution of the immune landscape upon treatment. We studied the expression of a handful of immune markers (CD3, CD8, CD68, PD-L1 and PD-1) in GBM tissues in 15 paired primary and recurrent GBM. In five selected patients, we used Nanostring Digital Spatial Profiling (DSP) to obtain simultaneous assessments of multiple biomarkers both within the tumor and the microenvironment in paired primary and recurrent GBM. Our results suggest that the evolution of the immune landscape between paired primary and recurrent GBM tumors is highly heterogeneous. However, our study identifies B3-H7 and HLA-DR as potential targets in primary and recurrent GBM. Spatial profiling of immune markers from matched primary and recurrent GBM shows a nonlinear complex evolution during the progression of cancer. Nonetheless, our study demonstrated a global increase in macrophages, and revealed differential localization of some markers, such as B7-H3 and HLA-DR, between GBM and its TME. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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18 pages, 2674 KiB

Open AccessArticle

Differences in Tumor Growth and Differentiation in NSG and Humanized-BLT Mice; Analysis of Human vs. Humanized-BLT-Derived NK Expansion and Functions

by Kawaljit Kaur and Anahid Jewett

Cancers 2023, 15(1), 112; https://doi.org/10.3390/cancers15010112 - 24 Dec 2022

Cited by 2 | Viewed by 2010

Abstract

There is significant interest and debate regarding the best mouse model of human disease, since studies in wild-type mice may not always recapitulate human diseases. The NSG mouse model has been one of the most commonly used mouse models to study cancer; however, this mouse model, even though it has several advantages in regard to the ease of tumor implantation and financial feasibility, does not represent human disease due to the immunodeficient nature of this model. In this study, we performed oral and pancreatic tumor studies in NSG and hu-BLT mice and found several distinguishing features that make hu-BLT model more suitable for studying human cancer. In addition, we compared the immune function of humans to hu-BLT mice to understand the differences and similarities of the models. Oral and pancreatic cancer stem cells were implanted in NSG and hu-BLT mice. Both tumors grew robustly in NSG mice and killed them within a short period of time. On the contrary, unlike NSG mice, tumor-bearing hu-BLT mice survived longer, grew smaller tumors, and the grown tumors exhibited lower rates of expansion, with a higher surface expression of MHC-class I and lower NK cell-mediated cytotoxicity that was previously shown to have more of a differentiated phenotype. Although the peripheral blood of hu-BLT mice in comparison to that of humans had lower percentages of NK cells and cytotoxic function, it mediated a higher secretion of IFN-γ, likely contributing to the differentiation of the tumor cells and subsequent decrease in the tumor size in the hu-BLT mice in comparison to the NSG mice. Spleen-derived hu-BLT mouse NK cells were able to expand in the presence of autologous osteoclasts and substantially increase both cytotoxicity and secretion of IFN-γ, similar to those seen in peripheral blood-derived human NK cells, indicating that NK cells from hu-BLT mice are capable of expansion and functional activation when activating signals are given. Thus, the many similarities between human and hu-BLT mouse immune systems make this mouse model more appropriate to study human cancer. In particular, it is well-suited for studies of allogeneic NK cell-based immunotherapy in cancer treatment. The advantages and challenges of hu-BLT mice in cancer studies are also discussed in this report. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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19 pages, 6231 KiB

Open AccessArticle

Integrated MRI–Immune–Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

by Giulia Mazzaschi, Alessandro Olivari, Antonio Pavarani, Costanza Anna Maria Lagrasta, Caterina Frati, Denise Madeddu, Bruno Lorusso, Silvia Dallasta, Chiara Tommasi, Antonino Musolino, Marcello Tiseo, Maria Michiara, Federico Quaini and Pellegrino Crafa

Cancers 2022, 14(13), 3249; https://doi.org/10.3390/cancers14133249 - 1 Jul 2022

Cited by 1 | Viewed by 1910

Abstract

Background: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features. Methods: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two-Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS). Results: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4^high vs. 13 months in V-CD4^low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMT^meth GB, while p53^mut appeared to condition a desert immune background. When individual genetic (MGMT^unmeth), MR imaging (mean ADC^low) and TIME (V-CD4+TILs^low) negative predictors were combined, median OS was 21 months (95% CI, 0–47.37) in patients displaying 0–1 risk factor and 13 months (95% CI 7.22–19.22) in the presence of 2–3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26–9.09). Conclusion: Interlacing MRI–immune–genetic features may provide highly significant risk-stratification models in GB patients. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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23 pages, 10180 KiB

Open AccessArticle

Comparative Study of the Role of Interepithelial Mucosal Mast Cells in the Context of Intestinal Adenoma-Carcinoma Progression

by Tanja Groll, Miguel Silva, Rim Sabrina Jahan Sarker, Markus Tschurtschenthaler, Theresa Schnalzger, Carolin Mogler, Daniela Denk, Sebastian Schölch, Barbara U. Schraml, Jürgen Ruland, Roland Rad, Dieter Saur, Wilko Weichert, Moritz Jesinghaus, Kaspar Matiasek and Katja Steiger

Cancers 2022, 14(9), 2248; https://doi.org/10.3390/cancers14092248 - 30 Apr 2022

Cited by 4 | Viewed by 2548

Abstract

Mast cells (MCs) are crucial players in the relationship between the tumor microenvironment (TME) and cancer cells and have been shown to influence angiogenesis and progression of human colorectal cancer (CRC). However, the role of MCs in the TME is controversially discussed as either pro- or anti-tumorigenic. Genetically engineered mouse models (GEMMs) are the most frequently used in vivo models for human CRC research. In the murine intestine there are at least three different MC subtypes: interepithelial mucosal mast cells (ieMMCs), lamina proprial mucosal mast cells (lpMMCs) and connective tissue mast cells (CTMCs). Interepithelial mucosal mast cells (ieMMCs) in (pre-)neoplastic intestinal formalin-fixed paraffin-embedded (FFPE) specimens of mouse models (total lesions n = 274) and human patients (n = 104) were immunohistochemically identified and semiquantitatively scored. Scores were analyzed along the adenoma-carcinoma sequence in humans and 12 GEMMs of small and large intestinal cancer. The presence of ieMMCs was a common finding in intestinal adenomas and carcinomas in mice and humans. The number of ieMMCs decreased in the course of colonic adenoma-carcinoma sequence in both species (p < 0.001). However, this dynamic cellular state was not observed for small intestinal murine tumors. Furthermore, ieMMC scores were higher in GEMMs with altered Wnt signaling (active β-catenin) than in GEMMs with altered MAPK signaling and wildtypes (WT). In conclusion, we hypothesize that, besides stromal MCs (lpMMCs/CTMCs), particularly the ieMMC subset is important for onset and progression of intestinal neoplasia and may interact with the adjacent neoplastic epithelial cells in dependence on the molecular environment. Moreover, our study indicates the need for adequate GEMMs for the investigation of the intestinal immunologic TME. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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18 pages, 2539 KiB

Open AccessArticle

Characterizing the Inflammatory Microenvironment in K14-HPV16 Transgenic Mice: Mast Cell Infiltration and MicroRNA Expression

by Alexandra C. Costa, Joana M. O. Santos, Beatriz Medeiros-Fonseca, Paula A. Oliveira, Margarida M. S. M. Bastos, Haissa O. Brito, Rui M. Gil da Costa and Rui Medeiros

Cancers 2022, 14(9), 2216; https://doi.org/10.3390/cancers14092216 - 28 Apr 2022

Cited by 4 | Viewed by 2138

Abstract

High-risk human papillomavirus (HPV) is the etiologic agent of several types of cancer. Mast cells’ role as either a driving or opposing force for cancer progression remains controversial. MicroRNAs are dysregulated in several HPV-induced cancers, and can influence mast cell biology. The aim of this study was to evaluate mast cell infiltration and to identify microRNAs potentially regulating this process. Transgenic male mice (K14-HPV16; HPV⁺) and matched wild-type mice (HPV⁻) received 7,12-Dimethylbenz[a]anthracene (DMBA) (or vehicle) over 17 weeks. Following euthanasia, chest skin and ear tissue samples were collected. Mast cell infiltration was evaluated by immunohistochemistry. MicroRNAs associated with mast cell infiltration were identified using bioinformatic tools. MicroRNA and mRNA relative expression was evaluated by RT-qPCR. Immunohistochemistry showed increased mast cell infiltration in HPV⁺ mice (p < 0.001). DMBA did not have any statistically significant influence on this distribution. Ear tissue of HPV⁺ mice showed increased mast cell infiltration (p < 0.01) when compared with chest skin samples. Additionally, reduced relative expression of miR-125b-5p (p = 0.008, 2^−ΔΔCt = 2.09) and miR-223-3p (p = 0.013, 2^−ΔΔCt = 4.42) seems to be associated with mast cell infiltration and increased expression of target gene Cxcl10. These results indicate that HPV16 may increase mast cell infiltration by down-regulating miR-223-3p and miR-125b-5p. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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Review

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15 pages, 1795 KiB

Open AccessReview

The Immune Cells in the Development of Oral Squamous Cell Carcinoma

by Vito Carlo Alberto Caponio, Khrystyna Zhurakivska, Lorenzo Lo Muzio, Giuseppe Troiano and Nicola Cirillo

Cancers 2023, 15(15), 3779; https://doi.org/10.3390/cancers15153779 - 26 Jul 2023

Cited by 3 | Viewed by 1954

Abstract

A still unresolved issue surrounding tumor formation concerns the role that the immune system plays in preventing the formation and progression of neoplasia, including oral squamous cell carcinoma (OSCC). Antitumor immunity has historically been seen as a critical barrier for cancer cells to develop, grow and spread, and this can be modulated using immunotherapies to achieve antitumor clinical responses. However, it has recently become clear that tumor-associated immunity, particularly the inflammatory microenvironment, has the paradoxical effect of enhancing tumorigenesis and progression. In this review, we discuss the multifaceted function of infiltrating immune cells in suppressing or promoting premalignancy and cancer. In particular, we report on the evidence supporting a role for T lymphocytes, dendritic cells, macrophages, and neutrophils in the development and progression of oral potentially malignant disorders (OPMD) and OSCC. We also draw attention to the clinical relevance of immune cell phenotypes and associated molecules for use as biomarkers and to the translatability of current research findings to improve classification systems and precision medicine in patients with OSCC. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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29 pages, 1833 KiB

Open AccessReview

Colorectal Cancer and Purinergic Signalling: An Overview

by Gabriela Gonçalves Roliano, Juliana Hofstätter Azambuja, Veronica Toniazzo Brunetto, Hannah Elizabeth Butterfield, Antonio Nochi Kalil and Elizandra Braganhol

Cancers 2022, 14(19), 4887; https://doi.org/10.3390/cancers14194887 - 6 Oct 2022

Cited by 8 | Viewed by 2822

Abstract

Colorectal cancer (CRC) is among the most common cancers and exhibits a high fatality rate. Gut inflammation is related to CRC, with loss of homeostasis in immune cell activities. The cells of the innate and adaptive immune system, including macrophages, neutrophils, mast cells, and lymphocytes, are present in most solid tumors. Purinergic signaling allows for communication between immune cells within the tumor microenvironment (TME) and can alter the TME to promote tumor progression. This system is regulated by the availability of extracellular purines to activate purinoceptors (P1 and P2) and is tightly controlled by ectonucleotidases (E-NPP, CD73/CD39, ADA) and kinases, which interact with and modify nucleotides and nucleosides availability. In this review, we compiled articles detailing the relationship of the purinergic system with CRC progression. We found that increased expression of CD73 leads to the suppression of effector immune cell functions and tumor progression in CRC. The P1 family purinoceptors A1, A2A, and A2B were positively associated with tumor progression, but A2B resulted in increased cancer cell apoptosis. The P2 family purinoceptors P2X5, P2X7, P2Y₂, P2Y₆, and P2Y₁₂ were factors primarily associated with promoting CRC progression. In summary, CD39/CD73 axis and the purinergic receptors exhibit diagnostic and prognostic value and have potential as therapeutic targets in CRC. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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21 pages, 1864 KiB

Open AccessReview

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity

by Md Nabiul Hasan, Okan Capuk, Shivani M. Patel and Dandan Sun

Cancers 2022, 14(14), 3331; https://doi.org/10.3390/cancers14143331 - 8 Jul 2022

Cited by 18 | Viewed by 4026

Abstract

Cancer cells possess a high metabolic demand for their rapid proliferation, survival, and progression and thus create an acidic and hypoxic tumor microenvironment (TME) deprived of nutrients. Moreover, acidity within the TME is the central regulator of tumor immunity that influences the metabolism of the immune cells and orchestrates the local and systemic immunity, thus, the TME has a major impact on tumor progression and resistance to anti-cancer therapy. Specifically, myeloid cells, which include myeloid-derived suppressor cells (MDSC), dendritic cells, and tumor-associated macrophages (TAMs), often reprogram their energy metabolism, resulting in stimulating the angiogenesis and immunosuppression of tumors. This review summarizes the recent findings of glucose, amino acids, and fatty acid metabolism changes of the tumor-associated macrophages (TAMs), and how the altered metabolism shapes the TME and anti-tumor immunity. Multiple proton pumps/transporters are involved in maintaining the alkaline intracellular pH which is necessary for the glycolytic metabolism of the myeloid cells and acidic TME. We highlighted the roles of these proteins in modulating the cellular metabolism of TAMs and their potential as therapeutic targets for improving immune checkpoint therapy. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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27 pages, 1306 KiB

Open AccessReview

The Cellular Tumor Immune Microenvironment of Childhood Solid Cancers: Informing More Effective Immunotherapies

by Malcolm Holterhus, Bianca Altvater, Sareetha Kailayangiri and Claudia Rossig

Cancers 2022, 14(9), 2177; https://doi.org/10.3390/cancers14092177 - 27 Apr 2022

Cited by 2 | Viewed by 2445

Abstract

Common pediatric solid cancers fail to respond to standard immuno-oncology agents relying on preexisting adaptive antitumor immune responses. The adoptive transfer of tumor-antigen specific T cells, such as CAR-gene modified T cells, is an attractive strategy, but its efficacy has been limited. Evidence is accumulating that local barriers in the tumor microenvironment prevent the infiltration of T cells and impede therapeutic immune responses. A thorough understanding of the components of the functional compartment of the tumor microenvironment and their interaction could inform effective combination therapies and novel engineered therapeutics, driving immunotherapy towards its full potential in pediatric patients. This review summarizes current knowledge on the cellular composition and significance of the tumor microenvironment in common extracranial solid cancers of childhood and adolescence, such as embryonal tumors and bone and soft tissue sarcomas, with a focus on myeloid cell populations that are often present in abundance in these tumors. Strategies to (co)target immunosuppressive myeloid cell populations with pharmacological anticancer agents and with selective antagonists are presented, as well as novel concepts aiming to employ myeloid cells to cooperate with antitumor T cell responses. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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27 pages, 1208 KiB

Open AccessReview

The Bone Marrow Microenvironment in B-Cell Development and Malignancy

by Anastasia M. Hughes, Vincent Kuek, Rishi S. Kotecha and Laurence C. Cheung

Cancers 2022, 14(9), 2089; https://doi.org/10.3390/cancers14092089 - 22 Apr 2022

Cited by 11 | Viewed by 3703

Abstract

B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoietic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system. This process is tightly regulated by spatially distinct bone marrow niches where cells, including mesenchymal stem and progenitor cells, endothelial cells, osteoblasts, osteoclasts, and adipocytes, interact with B-cell progenitors to direct their proliferation and differentiation. Recently, the B-cell niche has been implicated in initiating and facilitating B-cell precursor acute lymphoblastic leukemia. Leukemic cells are also capable of remodeling the B-cell niche to promote their growth and survival and evade treatment. Here, we discuss the major cellular components of bone marrow niches for B lymphopoiesis and the role of the malignant B-cell niche in disease development, treatment resistance and relapse. Further understanding of the crosstalk between leukemic cells and bone marrow niche cells will enable development of additional therapeutic strategies that target the niches in order to hinder leukemia progression. Full article

(This article belongs to the Special Issue The Role of Immune Cells in the Tumor Microenvironment)

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